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Combination of Sulindac and Antimicrobial Eradication of Helicobacter pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

¹ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts; ² Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York; and ³ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: James G. Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, 16-825, 77 Massachusetts Avenue, Cambridge, MA 02139. Phone: 617-253-1757; Fax: 617-258-5708; E-mail: jgfox{at}mit.edu.

Key Words: sunlindac • gastric cancer • antimicrobials • Helicobacter pylori • gastrin receptor antagonist (YM022)

Helicobacter pylori infection causes severe dysplasia manifested as gastrointestinal intraepithelial neoplasia (GIN) after 28 weeks post–H. pylori infection (WPI) in cancer-prone, hypergastrinemic male INS-GAS mice. We examined the efficacy of the nonsteroidal anti-inflammatory drug sulindac (400 ppm in drinking water) alone, the CCK2/gastrin receptor antagonist YM022 (45 mg/kg/wk) alone, and sulindac or YM022 combined with H. pylori eradication therapy to prevent H. pylori–associated gastric cancer in male INS-GAS mice. Treatments started at 22 WPI, and mice were euthanized at 28 WPI. In uninfected mice, all treatments significantly delayed development of spontaneous GIN (P < 0.05). In H. pylori–infected mice, sulindac alone or YM022 alone had no protective effect on H. pylori–associated GIN. Importantly, sulindac exacerbated the severity of H. pylori–associated gastritis despite decreased gastric prostaglandin E₂ levels. However, sulindac combined with H. pylori antimicrobial eradication reduced the incidence of GIN (P < 0.05), whereas YM022 combined with antimicrobial eradication did not reduce GIN. In infected mice, sulindac or YM022 treatment did not alter gastric expression of the proinflammatory cytokines Ifn- and Tnf- and mucosal cell proliferation. Sulindac or YM022 combined with antimicrobial eradication down-regulated mRNA levels of Ifn- and Tnf- and mucosal cell proliferation (P < 0.05). We conclude that sulindac enhances H. pylori gastritis and may promote inflammation-mediated gastric carcinogenesis. The combination of sulindac and antimicrobial H. pylori eradication was beneficial for reducing proinflammatory cytokine mRNA in the stomach and preventing progression from severe dysplasia to gastric cancer in H. pylori–infected INS-GAS mice. [Cancer Res 2009;69(20):8166–74]